Involvement of TR3/Nur77 translocation to the endoplasmic reticulum in ER stress-induced apoptosis

Retinoid-related molecules (RRM) are novel agents with tumor-selective cytotoxic/antiproliferative activity, a different mechanism of action from classic retinoids and no cross-resistance with other chemotherapeutics. ST1926 and CD437 are prototypic RRMs, with the former currently undergoing phase I clinical trials. We show here that ST1926, CD437, and active congeners cause DNA damage. Cellular and subcellular COMET assays, H2AX phosphorylation (;-H2AX), and scoring of chromosome aberrations indicate that active RRMs produce DNA double-strand breaks (DSB) and chromosomal lesions in NB4, an acute myeloid leukemia (AML) cell line characterized by high sensitivity to RRMs. There is a direct quantitative correlation between the levels of DSBs and the cytotoxic/antiproliferative effects induced by RRMs. NB4.437r blasts, which are selectively resistant to RRMs, do not show any sign of DNA damage after treatment with ST1926, CD437, and analogues. DNA damage is the major mechanism underlying the antileukemic activity of RRMs in NB4 and other AML cell lines. In accordance with the S-phase specificity of the cytotoxic and antiproliferative responses of AML cells to RRMs, increases in DSBs are maximal during the S phase of the cell cycle. Induction of DSBs precedes inhibition of DNA replication and is associated with rapid activation of ataxia telangectasia mutated, ataxia telangectasia RAD3-related, and DNAdependent protein kinases with subsequent stimulation of the p38 mitogen-activated protein kinase. Inhibition of ataxia telangectasia mutated and DNA-dependent protein kinases reduces phosphorylation of H2AX. Cells defective for homologous recombination are particularly sensitive to ST1926, indicating that this process is important for the protection of cells from the RRM-dependent DNA damage and cytotoxicity. [Mol Cancer Ther 2008;7(9):2941 -54]

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“…Resistance to RRMs is not due to differences in the 8 C. Pisano, unpublished results. 9 Unpublished results.…”

Section: Role Of Homologous Recombinationmentioning

confidence: 83%

Atypical retinoids ST1926 and CD437 are S-phase-specific agents causing DNA double-strand breaks: significance for the cytotoxic and antiproliferative activity

Valli¹,

Paroni²,

Francesco

et al. 2008

Molecular Cancer Therapeutics

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“…caspase-4, another caspase-1 family member, has the same function as caspase-12 in ERS-induced apoptosis in humans (53). Up-regulation of caspase-4 has been demonstrated in ers-mediated apoptosis in human bronchial epithelial cells (54), human neuroblastoma sKn-sH cells and human esophageal squamous carcinoma ec109 and ec9706 cells (55). caspase-3 is believed to be the main executioner caspase and is up-regulated in most apoptotic processes.…”

Section: Discussionmentioning

confidence: 99%

Involvement of endoplasmic reticulum stress in adenosine-induced human hepatoma HepG2 cell apoptosis

Ye²,

Huang³

et al. 2011

Oncol Rep

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Abstract. endoplasmic reticulum stress (ers)-mediated cell apoptosis has been implicated in the development of multiple diseases such as cancer, neurodegenerative diseases and ischemic reperfusion damage. previous studies have demonstrated the adenosine-induced apoptosis in several tumor cell lines. However, the role of ers in adenosine-induced human hepatoma Hepg2 cell apoptosis remains unclear. the present study was designed to determine whether ers is involved in adenosine-induced Hepg2 cell apoptosis. the Mtt assay was used to determine proliferation, and DApI staining of cell nuclei was performed to determine cell apoptosis. the translocation of cHop and caspase-3 was observed by immunofluorescence analysis, and the protein expression of CHOP, caspase-4 and caspase-3 was detected by Western blotting. the Mtt assay demonstrated that adenosine inhibited Hepg2 cell proliferation in a dose-dependent manner. DApI staining of cell nuclei and cell cycle analysis verified cell apoptosis. The immunofluorescence assay demonstrated that adenosine induced the translocation of cHop and of caspase-3 from the cytoplasm to the nucleus. Western blotting confirmed that cHop, caspase-4 and caspase-3 were up-regulated in Hepg2 cells after treatment with adenosine. However, JnK protein expression was not altered. These results show that ERS is involved in the adenosine-induced Hepg2 cell apoptosis.

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“…NGFI-B, an orphan member of the steroid/thyroid/ retinoid receptor superfamily of transcription factors in the nucleus (Liu et al 2008;Hamid et al 2008;Liang et al 2007;Eells et al 2000), plays an important role in cell proliferation and apoptosis (Kolluri et al 2008;Tao and Hancock 2008;Winoto 1997;Wilson et al 1991a, b). Recent investigation indicates that in cells treated with apoptosis inducers, NGFI-B translocates from nucleus to cytoplasm.…”

Section: Discussionmentioning

confidence: 99%

“…To maintain the normal architecture and function of myocardial tissues, various kinds of cell factors, such as transcription factors and signal transmitters, must be tightly regulated. Recent evidence indicates that nerve growth factor-induced clone B (NGFI-B), also known as Nur77 or TR3 (Lin et al 2004;Liang et al 2007), has been implicated as a mediator of cell apoptosis induced by mitochondria (Li et al 2000). However, the mechanism remains unclear.…”

mentioning

confidence: 99%

NGFI-B targets mitochondria and induces cardiomyocyte apoptosis in restraint-stressed rats by mediating energy metabolism disorder

Wang¹,

Liu²,

Kong³

et al. 2009

Cell Stress and Chaperones

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NGFI-B/Nur77/TR3, originally identified as an immediate-early gene rapidly induced by serum and growth factors, is a member of the steroid hormone nuclear receptor superfamily with no identified endogenous ligand. NGFI-B induces apoptosis in a number of cell lineages exposed to proapoptotic stimuli by directly targeting the mitochondria, inducing cytochrome c release. The present study was designed to determine the role of NGFI-B in cardiomyocytes of restraintstressed rats. The NGFI-B content was increased in mitochondria and reduced in plasma as apoptosis increased. Analysis showed that NGFI-B induces cardiomyocyte apoptosis in restraint-stressed rats by mediating mitochondrial energy metabolism disorder. Several novel mitochondrial proteins, which correlate with NGFI-B, were reported in cardiomyocyte apoptosis of restraint-stressed rats. Five proteins associated with NGFI-B participate directly in mitochondrial energy metabolism. Studies of mitochondrial respiratory efficiency and ATP synthase activity strongly support the findings. These results provide significant information for comprehensively understanding the cellular mechanism of cardiovascular diseases.

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Involvement of TR3/Nur77 translocation to the endoplasmic reticulum in ER stress-induced apoptosis

Cited by 52 publications

References 38 publications

Atypical retinoids ST1926 and CD437 are S-phase-specific agents causing DNA double-strand breaks: significance for the cytotoxic and antiproliferative activity

Atypical retinoids ST1926 and CD437 are S-phase-specific agents causing DNA double-strand breaks: significance for the cytotoxic and antiproliferative activity

Involvement of endoplasmic reticulum stress in adenosine-induced human hepatoma HepG2 cell apoptosis

NGFI-B targets mitochondria and induces cardiomyocyte apoptosis in restraint-stressed rats by mediating energy metabolism disorder

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